Postnatal knockdown of dok‐7 gene expression in mice causes structural defects in neuromuscular synapses and myasthenic pathology

The neuromuscular junction (NMJ) is a synapse between a motor neuron and skeletal muscle and is required for muscle contraction. The formation and maintenance of NMJs are governed by the muscle‐specific receptor tyrosine kinase MuSK. We previously showed that the muscle cytoplasmic protein Dok‐7 is an essential activator of MuSK. Indeed, mice lacking either Dok‐7 or MuSK form no NMJs, and defects in the human DOK7 gene underlie a congenital myasthenic syndrome (an NMJ disorder). However, it remains unproven whether Dok‐7 is required for the postnatal maintenance of NMJs. In this study, we generated recombinant adeno‐associated virus (AAV) vectors encoding short hairpin RNAs targeting the mouse dok‐7 gene (AAV‐shD7). Systemic administration of AAV‐shD7 into 2‐week‐old mice down‐regulated dok‐7 expression in muscle and induced myasthenic symptoms including reduction in body weight and motor function. Moreover, AAV‐shD7 treatment suppressed MuSK‐dependent gene expression of NMJ components and reduced the size of NMJs. These results demonstrate that correct, physiological levels of dok‐7 expression are required for the postnatal maintenance of NMJs. Dok‐7 is required for the embryonic formation of neuromuscular junction (NMJ), an essential synapse for muscle contraction, and its genetic mutations underlie an NMJ disorder, DOK7 myasthenia. We demonstrate that postnatal knockdown of dok‐7 gene expression in mice causes structural defects in NMJs and myasthenic symptoms including reduction in body weight and motor function. Thus, correct physiological levels of dok‐7 expression are required for the postnatal maintenance of NMJs, implying its relevance in myasthenia.